HIV Drugs Prevent Type 2 Diabetes, May Be Path to New Therapy

Pam Harrison

October 22, 2020

A class of drugs long used to treat HIV and hepatitis B viral infections appears to prevent the development of diabetes in a substantial proportion of patients who take these agents, an analysis of multiple databases has shown.

"Nucleoside reverse-transcriptase inhibitors (NRTIs), drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation," Jayakrishna Ambati, MD, University of Virginia School of Medicine, Charlottesville, Virginia, and colleagues write in their article, published recently in Nature Communications.

"[We showed that] the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure.... These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes," they say.

The researchers made a small chemical modification to NRTIs that led to their developing a new class of drugs, which they have termed "kamuvudines." Kamuvudines are nontoxic derivatives of NRTIs, Ambati told Medscape Medical News.

"People take NRTIs because they need to live with HIV, but giving them to the general population is not a great idea because of the toxicities associated with long-term NRTI use.

"So our focus is not to go forward specifically with NRTIs but rather with these new molecules that are far less toxic, and that is how we envision a clinical trial going forward," Ambati noted.

Researchers Screened Five Databases of >100,000 Patients

Ambati and colleagues analyzed information from five databases in which patients who had been exposed to an NRTI but who had not previously been diagnosed with type 2 diabetes were assessed for the subsequent development of diabetes over varying time intervals. In one, the Veterans Health Administration (VHA) database ― from the largest integrated healthcare system in the United States ― the analysis spanned a period of 17 years.

Of 79,744 patients with a confirmed diagnosis of HIV or hepatitis B in the VHA database, the risk for type 2 diabetes was reduced by 34% among NRTI users compared with nonusers after adjusting for potential confounders (P < .0001).

The reduction in diabetes risk was similar among HIV-positive and hepatitis B–positive patients.

These results were reaffirmed by further analyses of four other databases, the investigators report. One of these, the employer-based health insurance Truven database, had data on 23,634 patients who had been diagnosed with HIV or hepatitis B. After adjusting for potential confounders, NRTI users had a 39% lower risk of developing type 2 diabetes compared to nonusers (P < .0001).

The risk of developing type 2 diabetes was somewhat lower among NRTI users in the Pearl Diver database, which includes predominantly private health insurance claims. Of 16,045 patients diagnosed with HIV or hepatitis B included in this database, the risk for type 2 diabetes was 26% lower among NRTI users compared to nonusers (P = .004).

A similar magnitude of risk reduction was seen in the analysis of the Clinformatics dataset. Among 6341 users of NRTIs, the risk for type 2 diabetes was 27% lower than it was for nonusers (P = .009).

The least reduction in diabetes risk was in the Medicare database, in which only 3097 patients had been diagnosed with either HIV or hepatitis B. Among these patients, the risk for diabetes was 17% lower among NRTI users than it was for nonusers (P = .137).

One Third Reduction Across Multiple Databases Enhances Confidence

"Collectively, among 128,861 patients with HIV-1 or hepatitis B, users of NRTIs had a 33% reduced hazard of developing type 2 diabetes," Ambati and colleagues emphasize.

"The fact that the protective effect against the development of diabetes was replicated in multiple databases in studies from multiple institutions enhances confidence in the results," Ambati noted in a statement from the University of Virginia.

Ambati and colleagues also showed that the NRTI lamivudine (3TC) restores insulin sensitivity in human cells from type 2 diabetes patients.

That drug prevented induction of insulin resistance in human cells from people who did not have diabetes. It also prevented inflammasome activation in mice fed a high-fat diet.

"These investigations of human cell, mouse and population database systems collectively suggest a potential beneficial effect of NRTIs in forestalling diabetes onset," they stress.

Trial Assessing Kamuvudines Slated to Begin Next Year

In the interview with Medscape Medical News, Ambati explained that inflammasomes are protein complexes that form a large superstructure within the cell. "When activated, they lead to the production of some very powerful inflammatory cytokines, including interleukin (IL)-1β and IL-18."

Although there are many different types of inflammasomes, the one implicated in type 2 diabetes, as well as many other chronic diseases, including macular degeneration, is the NLRP3 inflammasome.

Activation of this molecule promotes insulin resistance, a key driver of type 2 diabetes, he explained.

Importantly, previous research (https://pubmed.ncbi.nlm.nih.gov/25414314/) showed that the way the NRTIs block this inflammasome has nothing to do with their anti-HIV activity.

After making a small chemical modification in the NRTIs, Ambati and colleagues were able to show that the resulting agents, which they have dubbed "kamuvudines," are able to block inflammasome activation independently of their antiviral effects.

They hope that this modification will reduce the toxicities associated with the agents. This would be necessary if kamuvudines were to be more widely used in a noninfected, healthier population, Ambati stressed.

Ambati and his colleague, Paul Ashton, PhD, cofounder of Inflammasone Therapeutics, plan a clinical trial with one of these kamuvudines in macular degeneration, which they hope will begin early next year.

"We are trying to pick a disease where we can show efficacy fairly quickly in a small number of people," Ashton explained to Medscape Medical News.

"We're very enthusiastic about this as it looks really, really promising."

Ambati and Ashton cofounded Inflammasone Therapeutics, located in Boston, Massachusetts. Ashton is the CEO of the company.

Nat Commun. Published online September 23, 2020. Full text

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